DE2712609A1 - LOCAL MEDICINE APPLICATION MATERIALS (CARRIERS) WITH INCREASED PENETRATION - Google Patents

Description

1 BERLIN 3S MÖNCHEN 0

Dr. RUSCHKE & PARTNER ZZSZ

PAT

ENTANWaLTB ₇₁₂₆₀₉

BERLIN - MONKS »' LAQUa

Τ «Ιί || ΐ

TELEX: HIM * 3

TELEX: 5227f7

Linnesota Lining ana i-anuf act urine; Company, baint Paul, i-iinnesota ^ 51 ^ 1, V.St.A «,

Locally applicable Araneimmittel-Aufbrinrun-rsniassen (i'räger) with

increased penetration

The invention relates to pharmaceuticals containing wet for local application to the skin and hate them or thin layers bugs, in particular, the invention relates to pharmaceuticals containing wet and thin layers with increased i ^! transfer use of the drug through overlaying.

I'herapeutiscia hate effective thin ochichLen-forming, which are suitable for topical application and contain an .emulsion of polyvinylidene chloride or polyethylene and a drug, are known from Gj-Po 1 215 2 ^ 5. A similar use of iolyethylene is described in the Dutch application 6 büy b> b voi '^ e. \:. Ciilc gen

ORIGINAL INSPECTED

there is a certain aversion to the use of the facilities of the proposed cash register for the haiogenated connections. Furthermore, the rate of drug absorption from these registers may be less than desired. It would be advantageous to be able to use such liquid drugs to apply and achieve increased levels of absorption. The present invention relates to hats containing hedge drugs for local application to the skin, which form a continuous, flexible, non-sticky and essentially non-breaking thin layer or film there; These hats contain an aqueous emulsion with an aqueous phase, a first dispersion phase, which consists essentially of a pharmaceutically acceptable, water-soluble, thin layer-forming polymer with a glass transition temperature Tg between about ( 1 ° C and 37 ° O) and a second dispersion phase , which consists essentially of a | solution of a drug in a pharmaceutically acceptable ^ non-volatile, water-insoluble solvent for this drug, the above-mentioned solvent behaving largely as a weight solvent to the water-soluble polymer of the first dispersion phase and being insoluble therein and said drug has a coefficient of solubility of at least about 10 between said water-insoluble solvent and water.

It has been found that a drug-containing composition for local application is obtained by preparing a dispersion, the two dispersed pharmaceutically acceptable

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-J-

Contains water-insoluble phases, the first phase being a polymeric substance and the second a represents a non-volatile solvent for the selected drug. In preferred embodiments of the invention is also contain a pharmaceutically acceptable dispersed hydrophilic polymeric substance that increases the viscosity of the hate and can help to protect the dispersion of the water-insoluble phases from flocculation. This may explain at least a partial explanation for the ease with which the invention hate being removed by water after its application to the skin Can be used even if under non-aqueous for hours Conditions were noted as they are flexible and not sticky as dry hate. Here are the terms water-insoluble polymer, solvent and water-soluble polymer indicate the first dispersion phase, the second Dispersion phase and the preferably dispersed hydrophilic polymer, which is either soluble or in the form of a gel can; furthermore, are pharmaceutically acceptable throughout the description, examples and claims? Substances meant.

The compositions according to the invention usually dry, i.e. they quickly form a thin layer after application to the skin, inside half of about 4 to 6 minutes when they are in a ratio of j

■ ■ 2 i

about 2 mgm per cm can be applied.

The compositions according to the invention usually contain emulsions of water-insoluble polymers (30 to 75 % solids

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tend) in a range of Ίο to ιϋ percent by weight of the total mass, preferably Ί ^ to 60 percent by weight of the total mass, and 5 to 25 percent water-insoluble non-volatile solvent for the drug. Preferably, the invention also contains Ί.5 to 1.5 percent based on the total weight of the hasse of dispersed hydrophilic polymer. The amount of drug used is dependent both on the desired total dose and on a given rate of absorption and is usually up to ΊΟ % of the amount of the water-insoluble solvent which is included for this purpose.

The registers of the invention are best made by dissolving the drug in a suitable solvent, if necessary, heating within the ötabilitatsgrenzen des Drug and emulsifying the solution in a previously prepared or commercially available emulsion of a water-insoluble, polymers forming thin layers.

It is possible to use highly soluble drugs in an emulsion] to disperse a suitable solvent; however, since the preferred solvents tend to be oily in character, is a previous loosening is preferable.

Hydrophilic polymeric substances are usually rapidly dispersed in the emulsion with stirring. Other substances which can optionally be added, are used to control the pü value, preferably in an acidic, skin-compatible one

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ORIGINAL

Area ,, or it is about liinuiyierunjrsiamittel for dispersion the solvent or, if necessary, pigments, dyes, moisture-retaining agents, fragrances and preservatives.

Emulsions are used to incorporate the water-insoluble Polymers are used because they have a relatively high solids content and to use polymers with a wide range of chemical structures without using volatile organic ones .Solvent. It is usually beneficial to nonioniscae to use surface-active substances or emulsifiers, since they are less sensitive; en over ioids of the pH - in the acidic range and usually not irritating to the skin are. The term "emulsion" as used herein includes those emulsions formed by emulsion and suspension polymerization natural latex particles and euulsions, which have been prepared by the dispersion process.

The medium in which the emulsion phases are dispersed is mainly water and especially water used in the dispersions of hydrophilic polymeric substances. It can contain pharmaceutically acceptable water-soluble excipients such as glycerin, ethylene glycol and propylene glycol. The amount of water-compatible drug carrier that may be present in the hedium depends on the particular drug or polymer used and on the ability of the emulsion to tolerate the drug carrier. In general, at least ^ J > of the medium are water, preferred

7.09838 / 1024 ORIGINAL INSPECTED

wise at least ^r / t >> ·

Many water-insoluble polymers can be used for the first dispersed layer in the ϊ-jars according to the invention. Suitable water-insoluble polymers form thin ochichten at temperatures below 37 G ₁ that is, below the ^human, body temperature when thin i are applied to a surface. Preference is given to polymers with a glass transition temperature

doors (Tg after determination by differential thermal analysis) between about O C and 35 C used, polymers with lower Glass over ^ temperatures are usually sticky and those with higher glass transition temperatures are too brittle. Among the typical lionomers that are used to produce water-insoluble Go or homopolymers used by emulsion polymerization include acrylonitrile, butadiene, chloroprene, isoprene, alkyl acrylates, alkyl methacrylates, styrene, vinyl acetate, Vinyl chloride and vinylidene chloride, ethylstyrene, isobutylene and Ethylenes can be used in copolymers. Suitable Lonomer pairs are ethylstyrene / butadiene, methylotyrene / vinyl methyl ether, Isobutylene / acrylonitrile, isobutylene / styrene, isobutylene / vinyl chloride and ethylene / sulfur dioxide.

Emulsions of many water-soluble polymers can also be prepared by dispersion techniques. Suitable emulsions, which are produced by Kispereion include as polymer vinyl type polyethylene, polyisoprene, poly (isobutylene-isoprene) and chlorinated poly (vinyl chloride) and as a polymer from non-

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Vinyl type polyurethane.

Preferred water-insoluble polymers include:
Acrylate polymers with glass transition stone temperatures in the desired
Area, especially ethyl or butyl acrylate / methyl methacrylate copolymers; Vinyl acetate polymers; Vinylidene chloride /
Vinyl acrylate, vinyl chloride or vinyl acetate copolymers;
Vinyl chloride, vinyl acetate or vinyl pyrrolidone / acrylate copolymers; Ethylene / vinyl chloride or vinyl acetate copolymers, and styrene / butadiene copolymers. The most preferred water-insoluble polymers are the acrylate polymers and
—Copolymers and styrene / butadiene copolymers.

Usually the emulsions contain the water-insoluble
Polymers 40 to 60 weight percent solids. However, are
also emulsions that are more than 60 percent or less than
Contains 40 percent solids, usable.

Many of the water-insoluble polymers require the inclusion \ of Plastifizierungsmittein so that the resulting thin
The layer is sufficiently flexible for use and the polymer has a minimum layer formation temperature of less than: 37 °. Plasticizers that are non-toxic to the skin

. are and will not be absorbed because of the oily drug!

'i

'containing phase, can be drawn during the formation of the emulsion-'

to form internal plasticizers. An intern , 'i

plasticized polymer contains a small amount of a copoly-!

: I.

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merized monomer, which plasticizes the rest of the polymer by its influence on the physical properties of the Polymers. An example of an internally plasticized water-insoluble one Polymer is the inclusion of, for example, 1 percent by weight of an acrylamide in the polymer.

The second dispersion phase in the hassen according to the invention is a generally oily solvent for the chosen drug, which is not significantly soluble in the first dispersion phase and the latter does not plasticize. This restriction is necessary, otherwise an excess of the second phase can be absorbed up to a point from the first phase, on which the latter would become tough or sticky and none sufficiently | could form a permanent thin layer. !

In general, the second dispersion phase of hydrophobic solvents for drugs is expediently formed from oils, ietteiii and waxes, ie esters or trihydric alcohols and long-chain alcohols with at least 8 carbon atoms, and from water-insoluble alcohols and ethers with at least 1 carbon atoms, such as polypropylene glycol and its Fe ttsäureäther, isosteeryl alcohol, etc. A particularly suitable substance is the polyoxypropylene fatty acid ether, which is available under the trademark Arlamol E.

Particularly suitable hydrophobic solvents for pharmaceuticals are natural oils and fats such as coconut oil, cotton seed oil, etc.

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Beef tallow, wool fat, etc., and hydrocarbon oils and low-melting ones Waxes such as iaraffin oil and ietrolat as well synthetic oils.

Discovery hates can be prepared using any drug which is preferentially soluble in the hydrophobic oily phase over the aqueous oily phase. The distribution constant, which characterizes the solution ratio between the two phases, should be at least fourth and preferably be much higher. Lipophilic steroid substances, such as V-i'luoro-11-ß, 17,? 0-trihydroxy-16 - ^ - methylpregna-1,4-diene-3,20-dione 21- (3,3-dimethyl) butanoate (known under the trade name dexamethasone tert-butyl acetate), liydrocortisone, hydrocortisone acetate, cortisone, 9-? luoro-11-ß, 16 - «(.- iy, 2i-tetrahydroxypregna-1,4-diene-3,2O-diene ( known under the trade name triamcinolin) and its acetonide, testosterone, foethyltestosterone, oestrone, oestradiol, ethinylestradiol, progesterone, 21-acetoxyprogesterone and the like are particularly suitable. Lipophilic vitamins such as A, D and E, and lipophilic antibiotics such as chlorotetracycline , Captan, Mitrofurazon and in particular antifum-ale active ingredients such as griseofulvin, thiabendazole (2- ( ^z f-thiazolyl) benzimidazole), undecylenic acid and nystatin and local anesthetics from the group of p-aminobenzoates, such as benzocaine (ethyl-p-sminobenzoate) and lidocaine (2,6-l) imethyl - *> - | diethylaminoacetanilide) can be used.

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Preferably, the hate according to the invention comprise a pharmaceutical Compatible hydrophilic polymer that is in the aqueous Phase is dispersed or dissolved. This polymer forms a thin layer, at least in the sense that when the Solution a thin layer of the residue remains. The length used can be 1.5 to 15 percent by weight of the total mass be. Usually the size is chosen so that it is ensured that the thin layer that is created with local application is ensured The Invention Fernsassen hate quickly washed off with water j can be. It is not certain, but it seems at least j probable that the first and second water-insoluble phases j

and the water phase including the hydrophilic polymer

! after drying a complex network of each other I

i pervasive phases supplies, allowing an entry to each

Phase can be possible both from the exposed surface j

the dried thin layer of the hate, as well as from the inner skin-lase boundary surface.

The water-soluble polymers generally used according to the invention include tragacanth rubber, pectin, Ghatti rubber, Gelatine, hydroxypropyl cellulose, hydroxyethyl cellulose, metharl

NatHwcarboxywethylcel luiose

cellulose, ethylhydroxypropyl cellulose / polyvinyl alcohol, polyvinylpyrrolidone, Polyethylene oxide, carboxypolymethylene and Methyl vinyl ether / foaleic anhydride copolymers. Preferred water-soluble polymers are cerboxy vinyl polymers (polyacrylic acid), hydroxypropyl cellulose, hydroxyethyl cellulose and cerboxypolyethylene. An abandonment of these water-soluble, thin

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Layer-forming polymers consists in the possibility of removal of the thin layers from the masses of the invention with water, they can also be added individually or in combination in increased amounts to thicken the rolled emulsion used, which is applied to the skin. Other thickeners can be used in the hats of the invention will. These means include inorganic substances, such as silica, bentonite and aluminum-i-magnesium silicate.

Modifying agents can also be used in the wet can be used. These include retention agents (e.g. urea), Buffers, preservatives, softeners, such as for example lanolin, glycerin, propylene glycol and sorbitol, fragrances and pigments. Insignificant additives can according to the invention can also be added to the consistency, homogeneity, spreadability, texture, appearance etc. such hate to improve.

The films of the invention are flexible, usually not glossy and essentially clear unless they contain pigments or dyes. That's why they're practical invisible on the surface of the skin. The thin films formed from the hate of the present invention have a remarkable one Expansion.

The hates according to the invention are applied by brushing onto the skin in a similar way to conventional creams

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- ΊέΤ-

would apply after drying is the area covered covered with a non-sticky, adhesive, invisible, polymeric thin layer.

When determining the masses according to the invention, it is appropriate to commercially available polymer emulsions, surface-active Substances, hydrophilic polymers and other chemicals to use. Some of the examples used in the following examples have the following characteristics:

Water-insoluble polymers

Primal B-52 is a 60/40 y · thylacrylate / diethyl methacrylate polymer with a glass transition temperature Tg of −t80 in an emulsion with 40 % solids content at a pH value of 8.5 with an anionic emulsifier. Zs is available from Iiohm and Haas Co., Philadelphia, Pennsylvania.

honflex 4 ^ 14 is a copolymer of ethylene and vinyl chloride with

third
an undisclosed / amide containing * »comonomer, a

Glass transition temperature Tg of 14 ° 0, emulsified with an anionic emulsifier and contains 47 % solids at a pH of 0.0 * 0.5 * ^ si:> t available from Monsanto Co., St. Louis, Hissouri. A similar polymer having a glass transition temperature Tg of 0 ⁰ C is available as honflex 4 ^ 00th

Pol.yco 2430 is a 67/33 copolymer of styrene / butadiene in an emulsion of pH 9-10 and a solids content of 40 "/ j. It is available from Borden Chemical Co.,

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ORIGINAL INSPECTED

Columbus, Ohio

Pοlyeο 26Q7 and 2619 are each internally plasticized or preplasticized polyvinyl chloride polymers with a pH value of 7 - ö and 9-10 and a solids content of 55 or 56} *>. They are also available from Borden Chemical Co.

Geon 652 is a Vinylcalorid / vinylidene chloride / i-thylacryiet copolymer having a glass transition temperature Tg of 15 C and contains at least 59.8 for chlorine in 52 ^ strength concentration at a pH - \ * ert of 6.0 with a sulfuric acid emulsifier . LS is available from Goodrich Chemical Co., Cleveland, Ohio.

Pliolit 160 is a 67/53 styrene / butadiene copolymer in an emulsion containing 5% solids and having a pH of 9.5. It is available from Goodyear Tire and Rubber Co., Akron, Ohio.

Rhoplex B - 15 is an acrylate polymer in a 46 % solids emulsion with a pH of 6.4 and a nonionic emulsifier. It is available from Rohm and Haas, Philadelphia, Pennsylvania.

Chemigum Latex 550 is a 40% emulsion with a pH-Y / ert of 8.1 of carboxylated butadiene / acrylonitrile. It is available from Goodyear Tire and Rubber Co.

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Polymers dispersible in water

Garbopol ^ 3 ^ - and ^ K) are oxyvinyl polymers available from i3.l · '. Goodrich Chemical Co., Cleveland, Ohio.

Klueel G is a hydroxypropyl cellulose available from Iiercules Inc., Wilming-fcon, Delaware.

Cellosize 300 is a hydroxyethyl cellulose available from Union Carbide Company, Wew York, New York.

Drug solvent

Isostceryl alcohol is available as Adol 66 from Ashland Chemical Co., Columbus, Ohio.

Arlamol E is a polyoxypropylene stearyl ether available from Imperial Chemical Industries, Wilmington, Delaware.

Other pharmaceutically-cosmetically acceptable oils and theirs companies of origin are:

Isopropyl myristate and isopropyl palmitate from Givaudan, Clifton, New Jersey.

Acetulan (acetylated lanolin alcohols) from Amerchol, Ldison, New Jersey.

Aldol VO (oleyl alcohol) and Starfol BG 100 (butyl stearate) from Ashland Chemicals, Columbus, Ohio.

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Silicone Oil 200 from i-'irraa Dow Corning ;, l.idland, i ^v .i.chigan.

liobane (squalene) from liobeco Chemical Co., New York, iiew York.

Unimate 601 (composition not disclosed, similar to isopropyl myristate) from Union Camp, Dover, Ohio.

Crodamol DA (diisopropyl adipate) from the company Oroda, liew York, i <ew York.

Ceraphyl 230 (diisopropyl adipate) from Van Dyk ix. Co., Belleville, New Jersey.

Surfactants, preservatives, etc.

The following substances are from Imperial Chemical

Industries available:

Tween 20 and Tween 40 are polyoxyethylene sorbitan monolaurate and monopalmitate, respectively.

ArIacel 20 and 40 are sorbitan monolaurate and monopalmitate, respectively. ArIacel 85 is sorbitan trioleate.
; Sorbo is a 7G # sorbitol solution

The effectiveness of the compositions according to the invention was after a by l-i.F. Caldman, B.J. Paulsen and "Ϊ. Hieuchi in J. Pharm. Sci., Volume 56, page 109Ö (1969), described standard test

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[averages. The process includes the measurement of the penetration part of the remedy through a sample of hairless mouse skin in full thick (all skin layer containing all skin layers). In These attempts will be a piece of cut out skin from the house about 3 x 5 cm over a salt reservoir with a surface area of

ρ
3.1 cm and a volume of 10 ml clamped and kept in contact with a saline solution, the prepared mixture containing the radioactively labeled drug is applied to the skin and the penetrated portion of the drug is followed by radio analysis. Using this method, the effectiveness of the wet kit can be determined by comparing it with the total amount of drug that has penetrated the skin, as measured by radiolysis using different carriers (or without a carrier). It is believed that larger amounts of the drug give a greater therapeutic effect.

The data in the following examples are parts by weight and temperatures in ⁰ G, unless stated otherwise.

example 1

Composition according to the invention with the designations A, B, C and D are emulsified using 0, 2.5, 5 and 10 parts, respectively Isostearyl alcohol produced. In either case, the isostearyl alcohol emulsion will be used (none is used for A) by heating isostearyl alcohol and Tween 20 and Arlacel 20 in

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- 47- -

a ratio of 10: 1: 0.5 together with 0.05 parts of tert-butyl acetate prepared dexamethasone at 70 ⁰ C and a sufficient Fienge water at 70 ⁰ O also un-cer added with stirring to reach 100 parts. An emulsion is obtained which is cooled to the temperature of the fluid. > 5 parts of i · onf lex 4514 latex, 0.8 parts of Garbopol 934 and 3.2 parts of 1Obiger sodium hydroxide solution (to neutralize Garbopol) are added successively to this emulsion while stirring. The various cash registers B, G and D according to the invention have only been compared, which contains no water-insoluble solvent for the dexamethasone and another series of Lassen i ,, F, ü and Ii produced analogously using i-ropylene glycol, one with water Miscible solvents, in quantities of 5, 10 and 20 parts. The results are expressed as the percentage release in 24 hours, ie penetration through the skin (see Table 1).

Table 1

ju \ g amount of the medicine, which in 24 btunden

Drug per part of skin passes through the skin

2.0 2.8% 7 9.5 ^ .0 2.1 2.7 2.7

47 / U g A. 52 0.9 B. 5ö 1.4 G 43 2.7 D. 47 4.1 E. 45 0.96 J? 46 0.95 G 45 1.25 H 1.21

709838/1024 ORIGINAL INSPECTtD

- ie ■ V.

It is obvious that the wet B, C and D are much more effective.

Example 2

A number of cash registers J, K and L according to the invention are shown under Use the proportions in parts per 100 according to Table 2 shown, the mixture being carried out in the sequence according to Example 1 and the test also mentioned there to penetrate the skin of the house.

Table 2 composition J K L. Dexamethasone - TBA 0.45 0.45 0.45 Decanol - - Isostearyl alcohol - 9, ö - Ariamol E. - - β, 9 Tween 40 1.3 - 1.8 Tween 20 - 1.3 - Arlacel ^ O - o, 9 - Arlecel 40 1.0 - - honflex 4514 52.8 4Ö, Ö ■ - rrimal B52 - - 18.0 Klucel GF - - 5.6 Garbopol 934 1.1 0.9 3.6 10 Jb NaOH 5.9 7.8 10.7 water up to 100 until 100 until 100 Penetration (jfc in 24 hours) 8th 9.5 9.6

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example

Ks are comparisons between a designated M according to the invention hate and hate ii and o, in which ir topylene glycol is used and does not contain any solvent for the medicine. The hates and results are in Table 3 listed.

l'abelle 3

Dexamethasone - I ¹ BA Arlamol E Propylene Glycol Primal B-52 Tween 40 Arlacel Sorbo
Garbopol Klucel GF isopropyl myristate 10 % NaOh water penetration tests (# per given time)

7 hours

8 hours 2 ^L V hours

0.1 0.1 0.1 10.1 - - - 10.1 - 20.0 20.0 20.0 1.0 1.0 1.0 1.0 1.0 1.0 7.0 7.0 7.0 0.7 0.7 0.7 5.5 5.5 5.5 0.5 - - 2.0 2.0 2.0 until 100 until 100 until 100 mm 0.2 1.6 1.0 - 7.7 2.7 0.7

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ORIGINAL INSPECTED

Example 4

A series of l · ', Q and ή denoted by the invention Hate that contain iiydrocortisone is compared to control substances that contain the same üi.eroid with l'ropylene glycol as Solvent (S) included and with a non-steroidal solvent (T) - The results are shown in Table 4.

Table 4

iHydrocortxson 1.0 1.0 1.0 1.0 15th 1.0 ArlaiuOl E 5.0 10 15th - 20.0 - Arlacel 85 1.0 1.0 1.0 - 2.0 - Propylene glycol - - - 1.0 - Primal B-52 20.0 20.0 29.0 2.0 20.0 Klucel Gj? 2.0 ■ d _t ü 2.0 6.0 2.0 Tween 40 1.0 1.0 1.0 until 100 - Garbopol 94G 2.0 2.0 2.0 2.0 10 ~, o NaOH o, 0 6.0 6.0 6.0 water until 100 until 100 until 100 until 100

/ o penetration in

24 hours 6.5 12.9 12.3

0.22

709838/1024 ORIGINAL INSPECTED

Example 5

Comparative tests are made between an inventive hasse / and a control composition V which does not contain any solvent for pharmaceuticals. The drug is the 2- (4-Thiazolyi) -benzimidazole (TBZ) antifungal gown. Hate were evaluated for their Iietnmungszone against Trichophyton rubrum (Aroerikanische 3atnn;. Lunix of Culture Types Hr 1d762) and L ^1. mentagrophytes (American Collection of Culture Types No. 4608) grown on agar tested.

The hates are established using the ratios as above and with the test results of Table 5

Table 5

TBZ

Arlamol E Tween 4O Arlacel 85 Garbopol 940 Primal B52 10 5 »NaOH V «ater hay zone T rubrum

T. mentagrophytes

1.0 1.0 10.0 - 1.0 - 1.0 - 1.0 1.0 20th 20th 3.0 3.0 until 100 until 100 40 mm. 35 mm $ 0 mm. 2S mm

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Example 6

A hatch according to the invention is made with a dissolution of 0.050 g N- (Trichloromethylthio) -4-cyclohexene-1,2-dicarboximide (available as Vem.de 89 RE from Vanderbilt Corp., Hew York,

New York) in 0.500 g Arlamol E with 0.050 g hydrocortisone (as i.v.
anti-inflammatory compound) using each

ι 0.050 g Tween 4Ό and Arlacel 85 together with 0.015 g isopropyl

myristat produced as an emollient. The combination j is dispersed in 2.58 g water and 0.350 g Sorbo with 0.050 g urea (as a moisturizer for the skin). By adding

1.00 g Primal B52, 0.035 6 Cerbopol 940, 0.167 g Klucel GF and ! A creamy paste is obtained with 0.1 g of 10% strength sodium hydroxide solution. she is tested for its inhibition against several organisms by attaching discs that are saturated with the cream of the surface of an inoculated medium in a Petri dish and then determining the inhibition zones. The organisms and zones of inhibition are Proteus vulgaris 0.5 mm, Staphylocoocus aureus 2.5 mm and Escherichia coli 2.5 mm.

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Claims (4)

η 3791 Claims u Cash registers containing a drug for local application to the skin with the formation of an uninterrupted, flexible, non-sticky and non-cracking thin splint, characterized in that they contain an aqueous emulsion with an aqueous phase, a first dispersed phase consisting essentially of pharmaceutical Compatible water-insoluble, thin layer-forming polymer with a glass transition temperature Tg between O ⁰ G and 37 ° C and of a second dispersed phase, which consists essentially of a solution of a drug in a pharmaceutically acceptable non-volatile water-insoluble solvent for the drug, the water-insoluble solvent is essentially a major solvent for and is not soluble in the water-insoluble polymer of the first dispersed phase and the drug has a coefficient of solubility of at least about 10 between the water-insoluble solvent and water. 2. hate according to claim 1, containing a medicament for local application to the skin with the formation of an uninterrupted 709838/1024 _0RIGlNAL inspected Broken firmly adhering, flexible, essentially non-sticky and non-cracking, water-removable thin layer, characterized in that they contain an aqueous emulsion which comprises an aqueous phase with 2.0 to pC percent by weight of water-soluble, thin layers forming Polymer, the percentages of the water-soluble polymer being based on the dry weight of the water-soluble polymer relative to the dry weight of the total water-soluble polymer and the first and second dispersion phases. 3. hate according to claim 1, characterized in that the drug is a steroid. 4. Wet according to claim 2, characterized in that the drug is a steroid. 709838/1024 ORIGINAL INSPECTED